African Americans have the highest incidence and death rates for colorectal cancer (CRC) of any major race or ethnicity in the United States. We have observed biological differences in CRCs at the level of DNA mismatch repair (MMR) that match the poor outcome observed in African American patients, including (a) half the presence of microsatellite instability (MSI) compared to Caucasians, a good prognostic marker seen in ~15% of all CRCs, and (b) twice the frequency of EMAST (elevated microsatellite alterations at selected tetranucleotide repeats), a form of tetranucleotide instability associated with inflammation, metastasis and lower survival, and observed in ~60% of CRCs. In this proposal, we hypothesize that the pro-inflammatory cytokine IL-6 is responsible for the observed biological effect of EMAST and its consequence of advanced stage and poor survival in African American CRC patients. Our preliminary data show that EMAST is driven by IL-6 through its trans-signaling pathway, shuttles the DNA MMR protein MSH3 out of the nucleus where it can no longer repair DNA to allow frameshift mutations to accumulate within DNA. We also show a defect in the number of granzyme B+ intraepithelial cells among CRCs from African Americans. In this proposal, we will: (1) test the hypothesis that IL-6 is concomitant with EMAST and portends reduced survival outcome, (2) test the hypothesis that aspirin/NSAIDs improve the outcome of EMAST CRC patients, and (3) determine if granzyme B-expressing cells is associated with EMAST and MSH3 inactivation, and reduced survival. Our proposal directly addresses Provocative Question #3, regarding tumor-associated immune responses and how it contributes to differences in cancer outcomes.